Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-04-25
2002-05-14
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000
Reexamination Certificate
active
06387402
ABSTRACT:
A subject-matter of the present invention is a pulverulent sorbitol of low hygroscopicity and of high specific surface which furthermore exhibits a low relative density, a specific particle size and an excellent ability to flow.
The invention also relates to a pulverulent sorbitol, the technical properties of which for use in direct compression are improved, and to a process for its preparation.
Sorbitol is a hexitol mainly used in the fields of food and pharmaceutical applications as a sweetening agent but also for its reduced calorific value and its acariogenicity.
Pulverulent sorbitol, just like other pulverulent polyols, such as xylitol or mannitol, is, for its part, commonly used as a pharmaceutical excipient, as a sweetener and texturizing agent in the food industry, and as an additive vehicle in industries of all types. However, it is a better excipient than xylitol and mannitol, in particular in compression, because of its specific ability to crystallize in the form of needle-shaped crystals which are directly compressible.
Generally, in order to have available a crystalline sorbitol of high compressive strength, every effort is made to manufacture a sorbitol of &ggr; crystalline form (the &agr; and &bgr; forms are particularly unstable) by processing a supersaturated solution of sorbitol, the &ggr; form of which represents at least 90%. However, even when it is crystallized in this, most stable, &ggr; form, the pulverulent sorbitol obtained conventionally exhibits a number of disadvantages, including that of being very hygroscopic.
This high hygroscopicity has the effect of rendering the flow of pulverulent sorbitol difficult, indeed even impossible, as soon as water uptake has occurred. Its use in direct compression is then found to be limited by this, requiring, for example, serious difficulties to be overcome in filling presses in the manufacture of lozenges or tablets.
In order to avoid this flow problem of pulverulent sorbitol, the preparation has been recommended of a sorbitol of low relative density and of coarser particle size, as disclosed in Patent FR 1,506,334.
However, it is established that the lower the bulk density of a pulverulent sorbitol, the greater the friability of the latter, that is to say the greater its sensitivity to a detrimental change in its particle size by mechanical action. In addition, the dissolution times of this pulverulent product of coarse particle size are generally too long and therefore unsuitable.
Finally, while the ability to flow is partially improved by the use of particles of such a particle size, the residual hygroscopic nature, which is still too high, in all cases renders the use of this pulverulent sorbitol out of the question when it is used in combination with ingredients or additives which are very sensitive to water.
It is also established that the ability to fix significant amounts of additive is a direct function of the specific surface of the said particles. The absorption capabilities of pulverulent sorbitol thus increase in proportion as its specific surface increases. However, it is known that the specific surface of the dense crystals of commercial &ggr; sorbitol is very low. Thus, for a particle size of between 500 and 1000 &mgr;m, it is very low, i.e. at most equal to 0.7 m
2
/g.
With the aim of preparing a pulverulent sorbitol exhibiting an improved particle size and a good ability to flow and satisfying the desired conditions of compressibility and friability, Patent Application FR 2,622,190 discloses a sorbitol powder comprising particles with a mean diameter of between 300 and 500 &mgr;m. However, the high bulk density and the relatively low specific surface of the said particles, of the order of 0.9 to 1.2 m
2
/g, are not in fact significantly modified by the manufacturing process employed, so that the pulverulent sorbitol thus obtained retains the same moisture absorption factor and the same solubility in water as the starting sorbitol powder.
Patent EP 32,288 discloses a &ggr; sorbitol polymorph, with a disintegrated and loose crystalline structure, which exhibits an improved hygroscopicity and satisfactory compressive properties. However, these specific properties only relate to a particle size fraction of between 250 and 841 &mgr;m (i.e. 20/60 mesh), the specific surface of which is, in any case, less than 2 m
2
/g.
It emerges, from everything which precedes, that there exists an unsatisfied need to have available a pulverulent sorbitol which simultaneously exhibits the advantages, generally incompatible, of low hygroscopicity, on the one hand, and of high specific surface, on the other hand, or of low bulk density, on the one hand, and of low friability, on the other hand, for a relatively low particle size.
It is therefore to the credit of the Applicant Company that it has reconciled all these objectives, hitherto regarded as irreconcilable, by devising and developing, at the cost of much research, a novel pulverulent sorbitol.
The pulverulent sorbitol in accordance with the invention is thus first of all characterized in that it exhibits:
a hygroscopicity value, determined according to a test A, of less than 2%, preferably of less than 1.7%,
a specific surface, determined according to the BET method, at least equal to 2 m
2
/g, preferably at least equal to 2.2 m
2
/g.
Its hygroscopicity, determined according to the test A, is preferably between 0.5 and 1.6%, preferably between 0.9 and 1.4%.
The test A consists in drawing up the isothermal curve for water sorption at 20° C. which expresses the percentage of water uptake of a pulverulent product, dehydrated beforehand, which is placed in an atmosphere of variable relative humidity and at a temperature of 20° C. The determination of the hygroscopicity of the pulverulent product will then be the percentage of water uptake at 60% equilibrium relative humidity (or 60% E.R.H.).
The specific surface is determined over the entire particle size distribution of the pulverulent sorbitol by virtue of a Quantachrome specific surface analyser based on a test of absorption of nitrogen on the surface of the product subjected to analysis, the technique described in the BET article, Surface Area by Nitrogen Absorption, by S. Brunauer et al. (Journal of the American Chemical Society, 60, 309, 1938), being followed.
It is particularly surprising that a pulverulent sorbitol can jointly exhibit a specific surface at least equal to 2 m
2
/g, preferably at least equal to 2.2 m
2
/g, and a hygroscopicity of less than 2%, preferably of less than 1.7%. This is because it is very conventionally accepted that the hygroscopicity of a pulverulent product increases with its specific surface, i.e. its surface exposed to the environment comprising water vapour.
In point of fact, the pulverulent sorbitol in accordance with the invention exhibits a high specific surface characteristic of a granulated product with, nevertheless, a low hygroscopicity characteristic of a product crystallized in a stable crystalline form.
By way of examples, the sorbitol sold by the company Merck under the name Sorbitol grade L exhibits a hygroscopicity of 2.4% at 60% ERH according to the test A, for a specific surface according to the BET method of 1.55 m
2
/g, and the sorbitol sold by the Applicant Company under the trade name Neosorb® P 60 W exhibits a hygroscopicity, under the same measuring conditions, with a value of 1.53% for a specific surface of less than 1 m
2
/g.
Surprisingly and unexpectedly, and in contrast to what was expected, the pulverulent sorbitol in accordance with the invention exhibits a strikingly lower hygroscopicity than that which is conventionally described for commercial pulverulent sorbitols exhibiting the highest specific surfaces. The result of this is that the pulverulent sorbitol in accordance with the invention has much better properties, in particular as additive vehicle, than a standard pulverulent sorbitol. These properties are due, at least in part, to the particularly high specific surface of this product.
The Applicant Company therefore regards as novel a pulve
Bouvier Frédéric
Labergerie Erik
Lefevre Philippe
Lis Jose
Moraly Franck
Henderson & Sturm LLP
Roquette Freres
Vollano Jean F.
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